1. Field of the Invention
The invention relates to therapeutic compositions for the treatment and/or curing of poison oak irritation. The invention also relates to processes of manufacturing such therapeutic compositions, and to processes of using such therapeutic compositions.
2. Prior Art
Chemically speaking, the greatest interest in Ceanothus species has been in studying the complex peptide alkaloids, which occur mainly at every low concentrations in the rootbark of several species.
Ceanothus americanus leaf extracts have been employed in the United States of America as a sedative, for asthma, as an antispasmodic and as an expectorant. [Clark, A. H., Amer. J. Pharm., 147-156 (1926).] Rootbark extracts of such species have been employed by the Cherokee Indians as a panacea for a wide variety of illnesses, as early as the year 1700 [Clark]. Rootbark extracts have been widely employed to hasten blood clotting [Clark]. Such species is known in the vernacular as Jersey Tea, Red Root and Wild Snowball.
Aqueous and chloroform extracts of C. americanus roots have been reported to be devoid of antimalarial activity when administered orally and/or subcutaneously to chicks infected with Plasmodium gallinaceum. [Spencer, C. F., F. R. Koniuszy, E. F. Rogers, J. Shavel, Jr., N. R. Easton, E. A. Kaczka, F. A. Kuel, Jr., R. F. Phillips, A. Walti, K. Folkers, C. Malanga and A. O. Seeler, Lloydia, 10:145 (1947)].
Most pharmacological studies carried out on C. americanus have been directed toward verifying the alleged hemostatic or antihemorrhagic effects of such plant. The first studies of such type were reported in 1927 by Groot who administered a hydroalcoholic extract prepared from C. americanus rootbark to a number of human subjects orally and reported a marked reduction in blood coagulation time, which commenced about 15 minutes following administration and persisted for about one hour. [Groot, J. T., J. Pharmacol. Exp. Ther., 30:275-291 (1927).] Several other studies in humans have seemingly confirmed such anticoagulant effect, either employing hydroalcoholic, total alkaloids or semi-purified alkaloid extracts of C. americanus rootbark. [Tharaldsen, S. E. and J. Krawetz, Amer. J. Physiol., 79:545-552 (1927); Tharaldsen, C. E. and J . Krawetz, J. Ophth., Otol., Laryngol., 31:226-235 (1927); Payne, R. J., Ann. Otol. Rhin. Laryngol., 35:769-790 (1926); Taylor, G. C., Amer. J. Pharm., 99:214-232 (1927); and Gibbs, O. S., J. Pharmacol. Exp. Ther., 36:173-177 (1929).] The hydroalcoholic extract has been administered to several hundred human subjects and no side effects have been reported. The usual decrease in clotting time produced by the extract in humans was from 25 to 50 percent. [Tharaldsen et al. I; Tharaldsen et al. II; Payne; Taylor; and Gibbs.] Hydroalcoholic extracts of rootbark and alkaloid fractions have been administered orally and/or subcutaneously to rats, guinea pigs, rabbits and dogs, with decreases in clotting time reported in all cases. [Lynch, T. A. and T. S. Miya, Dissertation Abstracts, 27:562 (1966); Groot; Tharaldsen et al. I; Tharaldsen et al. II; and Payne.] A single report in 1929 showed no effect on coagulation time of a hydroalcoholic extract of rootbark following oral administration to several human subjects at a dose of 80 ml per subject. [Gibbs] The author attributed such discrepancy to inappropriate means of determining coagulation time in the earlier studies.
In an attempt to identify the substances responsible for the reduction in clotting time, the effects of a hydroalcoholic extract of rootbark were compared with those of the acidic and neutral fractions, following oral administration to rats. The latter fraction was found to be inactive, whereas the two former fractions were active. It was shown that oxalic, malonic, succinic, orthophosphoric and pyrophosphoric acids were present in the active acid fraction and that all of them produced a reduction in clotting time in vitro. [Lynch]
A hydroalcoholic extract of rootbark was administered intragastrically to dogs at a dose of 125 ml daily for 19 days. No acute nausea and/or vomiting was noted. Kidney function tests were carried out on the dogs and were found to be normal during the testing period. [Koppanyi, T., J. Amer. Pharm. Ass., 17:528-529 (1928).]
Ceanothic acid, a trierpene present in C. americanus rootbark, has been reported to have no effect on clotting time when administered to dogs intravenously at doses of 100 and 300 mg/kg. [Julian, P. L., J. Pikl and R. Dawson, J. Amer. Chem. Soc., 60:77-79 (1938).]
A hydroalcoholic extract of rootbark has been reported to elicit marked hypotensive activity following i.v. administration to anesthetized dogs with no apparent effect on the heart. [Groot] However, a later report indicated that the total alkaloid fraction of rootbark had no effect on dog blood pressure when administered at doses of less than 5.0 mg/kg. At doses of 5 to 10 mg/kg there was only a transient hypotensive response and a slight increase in heart rate. [Roscoe, C. W. and N. A. Hall, J. Amer. Pharm. Ass., Sci. Ed., 49:108-112 (1960)]
U.S. Pat. No. 2,254,051 teaches that a crystalline extract of Ceanothus americanus was a blood coagulant.
An uncharacterized alkaloid (m.p. 183.degree.-186.degree.) isolated from C. americanus rootbark has been extensively studied for its pharmacologic effects. [Manian, A. A. and L. D. Edwards, Dissertation Abstracts, 16:2479 (1956).] The alkaloid had no local anesthetic, antihistaminic or hemolytic effects in laboratory animals and it did not affect uterine tissue or the smooth muscle of cattle carotid arteries. In rats, it displayed an LD.sub.50 (i.v.) of 96.4 mg/kg and in mice 90 to 100 mg/kg (i.v.). No mortalities resulted following oral administration of the alkaloid to rats at doses up to 1.0 gm/kg. The alkaloid was hypotensive when administered to normotensive dogs, cats and rats and was anthypertensive in hypertensive rats. The electrocardiogram indicated that the hypotension could have resulted from a cumulative cardiotoxic action. In isolated heart preparations, the alkaloid produced coronary vasodilator effects at low doses (rat, guinea pig and rabbit hearts). At 5.0 mcg doses, the alkaloid produced positive chronotropic, inotropic and tonotropic effects on the isolated rat heart. At larger doses there was a negative inotropic and negative chronotropic effect, with cardiac arrest. The alkaloid produced a vasodilator effect in the perfused rat hind limb preparation. When administered, i.p. to rats at 50 mg/kg, the alkaloid produced an antisecretory effect on unstimulated gastric secretions. At doses of 50 to 100 mg/kg given by the intraperitoneal route to rats, the alkaloid produced an antidiuretic effect, but was devoid of this activity when administered orally. Daily dosing with the alkaloid for 45 days (i.p., rats), produced extensive fibrous connective tissue formation and petechiae in the mesenteries and small intestine. Histopathological studies indicated marked changes in the pancreas, and stomach and slight lesions in the adrenal glands, kidney and dorsal aorta. [Manian et al.]
Concerning the species Ceanothus interrimus Hook et Arn., water and chloroform extracts prepared from either the root or rootbark of this species were shown to be devoid of antimalarial activity when administered orally to chicks infected with Pasmodium gallinaceium. [Spencer et al.]
Concerning the species Ceanothus velutinus Dougl., in 1905, Rooney described cases of dermatitis in subjects exposed to C. velutinus leaves. [Rooney, California State J. Med., (1905).] Such was later confirmed experimentally, with the toxic substance(s) demonstrated to be present in the leaves or in an ether extract of the leaves. [Richards, L. W. and E. V. Lynn, J. Amer. Pharm. ASs., 23:332-336 (1934).] Aqueous extracts prepared from the leaves failed to produce dermatitis in humans. [Richards et al.] An ether-insoluble alkaloid extract prepared from C. velutinus roots was administered intraduodenally to anesthetized dogs at a dose of 10 mg/kg and was shown to have no effect on blood pressure. The ether-soluble alkaloids were also devoid of hypotensive activity. [Roscoe et al.]